PDF(Pubmed)
Abstract：
Anaplastic thyroid carcinoma (ATC) is a rare but highly aggressive thyroid cancer with poor prognosis. Killing cancer cells by inducing DNA damage or blockage of DNA repair is a promising strategy for chemotherapy. It is reported that aldehyde-reactive alkoxyamines can capture the AP sites, one of the most common DNA lesions, and inhibit apurinic/apyrimidinic endonuclease 1(APE1)-mediated base excision repair (BER), leading to cell death. Whether this strategy can be employed for ATC treatment is rarely investigated. The aim of this study is to exploit GSH-responsive AP site capture reagent (AP probe-net), which responses to the elevated glutathione (GSH) levels in the tumor micro-environment (TME), releasing reactive alkoxyamine to trap AP sites and block the APE1-mediated BER for targeted anti-tumor activity against ATC. In vitro experiments, including MTT andγ-H2AX assays, demonstrate their selective cytotoxicity towards ATC cells over normal thyroid cells. Flow cytometry analysis suggests that AP probe-net arrests the cell cycle in the G2/M phase and induces apoptosis. Western blotting (WB) results show that the expression of apoptotic protein increased with the increased concentration of AP probe-net. Further in vivo experiments reveal that the AP probe-net has a good therapeutic effect on subcutaneous tumors of the ATC cells. In conclusion, taking advantage of the elevated GSH in TME, our study affords a new strategy for targeted chemotherapy of ATC with high selectivity and reduced adverse effects.
摘要：
间变性甲状腺癌（ATC）是一种罕见但高度侵袭性的甲状腺癌，预后不良。通过诱导DNA损伤或阻断DNA修复来杀死癌细胞是一种有希望的化疗策略。据报道，醛反应性烷氧基胺可以捕获AP位点，最常见的DNA损伤之一,并抑制嘌呤/嘧啶核酸内切酶1（APE1）介导的碱基切除修复（BER），导致细胞死亡。很少研究这种策略是否可以用于ATC治疗。本研究的目的是利用GSH响应性AP位点捕获试剂（AP探针网），对肿瘤微环境（TME）中谷胱甘肽（GSH）水平升高的反应，释放反应性烷氧基胺以捕获AP位点并阻断APE1介导的BER，从而具有针对ATC的靶向抗肿瘤活性。体外实验,包括MTT和γ-H2AX测定，证明它们对ATC细胞的选择性细胞毒性超过正常甲状腺细胞。流式细胞术分析表明，AP探针网将细胞周期阻滞在G2/M期并诱导细胞凋亡。Westernblotting(WB)结果表明，随着AP探针网浓度的增加，凋亡蛋白的表达增加。进一步的体内实验表明，AP探针网对ATC细胞的皮下肿瘤具有良好的治疗作用。总之,利用TME中升高的GSH，我们的研究为ATC的靶向化疗提供了一种高选择性和减少不良反应的新策略.
